Increased influenza severity in children in the wake of SARS‐CoV‐2

Abstract The SARS‐CoV‐2 pandemic and subsequent interruption of influenza circulation has lowered population immunity to influenza, especially among children with few prepandemic exposures. Using data from a prospective pediatric cohort study based in Managua, Nicaragua, we compared the incidence and severity of influenza A/H3N2 and influenza B/Victoria between 2022 and two prepandemic seasons. We found a higher incidence of A/H3N2 in older children in 2022 compared with pre‐2020 and a higher proportion of severe influenza in 2022, primarily among children aged 0–4, suggesting an influence of the SARS‐CoV‐2 pandemic on influenza incidence and severity in children.


| INTRODUCTION
In the 2 years following the emergence of SARS-CoV-2, global circulation of influenza was low. 1 This gap in influenza circulation, along with decreased uptake of influenza vaccination, has lowered population immunity to influenza, which could lead to increased severity of influenza epidemics. 2,3 Children experience symptomatic influenza infections more frequently than adults and bear a disproportionate portion of the burden of influenza. 4,5 In addition, children have fewer total lifetime influenza exposures and are normally exposed to influenza in the first few years of life, so they may be at even greater risk of severe influenza during rebound seasons due to fewer prior exposures and changes in the age patterns of first influenza exposure. 6 In 2022, influenza began to recirculate in much of the world with sporadic seasonality, limited antigenic diversity of circulating strains, and the absence of B/Yamagata circulation globally. 2,7 However, the severity of influenza in children in 2022 has not been compared with prior seasons, and the clinical impact of waning influenza immunity during the gap in influenza circulation has not been described. Using data from a prospective cohort study of children in Managua, Nicaragua, we describe the incidence and severity of influenza in F I G U R E 1 (A) Influenza incidence rate in the Nicaraguan Pediatric Influenza Cohort Study, by season. (B) Age distribution of A/H3N2 and B/Victoria cases, pre-2020 versus 2022 (Wilcoxon rank sum test). (C) Comparison of influenza incidence rate pre-2020 versus 2022, by age. (D) Frequency of severe influenza infection, pre-2020 vs. 2022 (Fisher's exact test). 2022 and examine whether the incidence and severity of symptomatic influenza infections is greater in 2022 compared with several prepandemic seasons.

| METHODS
The Nicaraguan Pediatric Influenza Cohort Study (NPICS) is a prospective pediatric cohort study based in Managua, Nicaragua, that enrolls healthy children aged 0-14. 8 The NPICS utilizes passive influenza surveillance through free medical care to enrolled participants; if enrolled children become ill, they are examined by study physicians and tested for influenza if they have pneumonia or severe respiratory disease, or if they meet age-based symptom criteria (Table S1). Combined nasal/oropharyngeal samples were obtained and tested for influenza using real-time reverse-transcription polymerase chain reaction (RT-PCR) using validated CDC protocols. 9 If positive for influenza, subtype or lineage was obtained following CDC protocols. 10 Both   Figure 1C). Vaccination rates in the cohort were low overall, and children were more likely to have been vaccinated for influenza in 2022 compared with pre-2020 seasons; 19 (9.6%) children were vaccinated in the 6 months prior to infection in 2022, compared with 15 (4.5%) children in the pre-2022 seasons ( p = 0.023). The symptomatic presentation of 2022 cases was similar to pre-2020 cases, with no differences in the frequency of subjective fever, cough, gastrointestinal (GI) symptoms, or Influenzalike-illness (ILI); however, objective fever, sore throat and headache were less frequently reported in 2022 cases than pre-2020 cases (Table S3). Children aged 0-14 were nearly three times more likely to experience a severe case of A/H3N2 in 2022 compared with the pre-2020 seasons. Of the 198 cases in 2022, seven (3.5%) of them were severe; of the 330 cases in the pre-2020 seasons, four (1.2%) of them were severe ( p = 0.111) ( Figure 1D, Table S4). Influenza cases were significantly more severe in children aged 0-4 in 2022; six of 87 (6.9%) cases were severe in 2022, compared with three of 189 (1.6%) cases in the pre-2020 seasons ( p = 0.030; Figure 1D).   Figure 1C). Influenza B/Victoria cases in 2022 were also more likely to have been vaccinated for influenza in the 6 months prior to infection (18.8% vs. 0.6%, p < 0.001). Compared with pre-2020 cases, 2022 cases had a higher frequency of many signs and symptoms, including objective fever, cough, and headache (Table S6). Influenza B/Victoria cases were not more severe than cases in the pre-2020 (p = 0.447; Figure 1D, Table S7). Analyses adjusting for age, sex, and comorbidities demonstrated comparable results (Table S8).

| DISCUSSION
Low circulation of influenza during the first 2 years of the SARS-CoV-2 pandemic was predicted to increase the incidence and clinical severity of influenza infections during rebound influenza epidemics due to decreased population immunity. We found that children infected with A/H3N2 in 2022 were a year older, on average than children infected with A/H3N2 in the pre-2020 seasons, possibly representing a delay in the timing of the first few lifetime influenza infections. Though this age pattern is unlikely to become entrenched without another multiyear gap in influenza circulation, it suggests that immunologic age as a function of exposure history may matter more than biologic age for the risk of influenza infections in young children.
Older children normally have some degree of immunity to influenza that is continually boosted by repeated childhood infections and seasonal circulation; we hypothesized that this immunity waned while influenza was not circulating and predicted we would see increased symptomatic influenza incidence in older children once influenza returned. We found an increase in A/H3N2 incidence in children aged 5-14 but not in children aged 0-4. The similar rate of influenza infection in young children between seasons suggests that the overall force of infection was likely similar, and the increase observed in older children supports the notion that waning influenza immunity due to SARS-CoV-2 may have increased either the underlying susceptibility to infection and/or the proportion of infections that were symptomatic and therefore detected. The total number of clinic visits and the portion of clinic visits that met testing criteria and that were associated with a positive influenza PCR remained relatively constant, suggesting that healthcare utilization patterns did not drastically change across the comparison ( Figure S1).
In addition to an increase in susceptibility to symptomatic influenza infection in older children, we also observed higher severity of Unlike with A/H3N2, the age distribution and incidence of B/Victoria cases in 2022 was not significantly different than the pre-2020 seasons, likely because 2-year gaps in influenza B circulation occur commonly in our setting. 11 Severe B/Victoria was more likely to occur in 2022 than in the pre-2020 B/Victoria seasons; however, one limitation of our study it that the small sample limits the statistical power of these comparisons.

| CONCLUSION
Using data from one of the largest and longest-running prospective pediatric cohorts of influenza, we found that 2022 A/H3N2 infections had higher incidence in older children, and 2022 infections were three to four times as likely to be severe compared with pre-2020 A/H3N2 infections. This increased severity may represent waning influenza immunity in children due to the SARS-CoV-2 pandemic. supervision; writing-review and editing. Aubree Gordon: Conceptualization; funding acquisition; investigation; methodology; project administration; resources; supervision; writing-review and editing.